This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Friedreich's ataxia is a progressive neurodegenerative disorder caused by the unstable hyper-expansion of GAA-TTC triplets in the first intron of the FXN gene, that encodes the essential protein frataxin. This mutation interferes with gene transcription and, based on the hypothesis that the acetylation status of core histones on the FXN gene might be responsible for its silencing, we have developed a new class of histone deacetylase (HDAC) inhibitors that reverse frataxin gene silencing in cell culture and in a mouse model of the disease. Through proteomic studies using an activity profiling probe we have identified HDAC3 as the target of our HDAC inhibitors, but the mechanism by which our molecules increase the expression of the FXN gene is unknown. HDAC3 is part of different protein complexes in vivo and interacts with various transcription factors. To help elucidate the molecular mechanism underlying the silencing and reactivation of FXN, we wish to identify HDAC3 interacting partners in the presence and absence of HDAC inhibitors. Currently there is no effective treatment for Friedreich?s ataxia and the study of the effect of HDAC inhibitors on HDAC3 complexes can lead to new and improved therapeutics for this devastating neurological disorder.